The present invention relates to adamantane derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1xcex2 (IL-1xcex2) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes, erythrocytes, erydiroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones and renal mesangial cells.
It would be desirable to make compounds effective as P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X7 receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of general formula 
wherein D represents CH2 or CH2CH2, preferably CH2;
E represents C(O)NH or, preferably, NHC(O);
R1 and R2 each independently represent a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, or an amino (NH2), nitro (NO2), C1-C6 alkyl or trifluoromethyl group;
R3 group of formula 
xe2x80x83X represents an oxygen or sulphur atom or a group NH, SO or SO2;
Y represents an oxygen or sulphur atom or a group NR11, SO or SO2;
Z represents a group xe2x80x94OH, xe2x80x94SH, xe2x80x94CO2H, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, xe2x80x94NR6R7, xe2x80x94C(O)NR8R9, imidazolyl, 1-methylimidazolyl, xe2x80x94N(R10)C(O)xe2x80x94C1-C6 alkyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxycarbonyloxy, xe2x80x94OC(O)NR12R13, xe2x80x94OCH2OC(O)R14, xe2x80x94OCH2OC(O)OR15 or xe2x80x94OC(O)OCH2OR16;
R4 represents a linear or branched C2-C6 alkylene group;
R5 represents a linear or branched C1-C6 alkylene group;
R6, R7, R8, R9, R10, R12 and R13 each independently represent a hydrogen atom, or a C1-C6 alkyl group optionally substituted by at least one hydroxyl group (e.g., one, two or three hydroxyl groups);
R11 represents a hydrogen atom, or a C1-C6 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from hydroxyl and C1-C6 alkoxy; and
R14, R15 and R16 each independently represent a C1-C6 alkyl group; with the provisos that (i) when E represents NHC(O), X represents O, S or NH and Y represents O, then Z represents xe2x80x94NR6R7 where R6 represents a hydrogen atom and R7 represents either a hydrogen atom or a C1-C6 alkyl group substituted by at least one hydroxyl group, and (ii) when E represents NHC(O), X represents O, S or NH, Y represents NH and
R5 represents CH2CH2, then Z is not xe2x80x94OH or imidazolyl;
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched. In the present invention, an alkyl group or moiety may contain up to 6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl.
Preferably, R1 and R2 each independently represent a hydrogen or halogen atom, or an amino, nitro, C1-C4 alkyl or trifluoromethyl group.
More preferably, R1 and R2 each independently represent a hydrogen, chlorine or bromine atom, or an amino, nitro, C1-C3 alkyl or trifluoromethyl group.
Most preferably, R1 and R2 each independently represent a hydrogen or chlorine atom.
Preferably X represents an oxygen atom or a group NH.
Preferably Z represents a group xe2x80x94OH, xe2x80x94SH, xe2x80x94CO2H, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4-alkylsulphinyl, C1-C4-alkylsulphonyl, xe2x80x94NR6R7, xe2x80x94C(O)NR8R9, imidazolyl, 1-methylimidazolyl, xe2x80x94N(R10)C(O)xe2x80x94C1-C4 alkyl, C1-C4 alkylcarbonyloxy, C1-C4 alkoxycarbonyloxy, xe2x80x94OC(O)NR12R13, xe2x80x94OCH2OC(O)R14, xe2x80x94OCH2OC(O)OR15 or xe2x80x94OC(O)OCH2OR16.
Particularly preferred groups Z include xe2x80x94OH, xe2x80x94CO2H, methoxy, methylthio, methylsulphinyl, methylsulphonyl, xe2x80x94NR6R7, xe2x80x94C(O)NR8R9, xe2x80x94N(R10)C(O)CH3, imidazolyl, 1-methylimidazolyl, C1-C4 alkylcarbonyloxy, C1-C4 alkoxycarbonyloxy, xe2x80x94OC(O)NR12R13, xe2x80x94OCH2OC(O)R14, xe2x80x94OCH2OC(O)OR15 and xe2x80x94OC(O)OCH2OR16.
R4 preferably represents a C2-C4 alkyl group, for example a linear alkyl group such as xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94.
R5 preferably represents a C1-C5 alkyl group, for example xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2CH(CH3)xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, xe2x80x94(CH2)2C(CH3)2xe2x80x94 or xe2x80x94CH2C(CH3)2xe2x80x94.
Preferably R6, R7, R8, R9, R10, R12 and R13 each independently represent a hydrogen atom, or a C1-C4 alkyl group optionally substituted by at least one hydroxyl group.
Y is conveniently a group NR11. It is preferred that R11 represents a hydrogen atom, or a C1-C4 alkyl group optionally substituted by at least one substituent independently selected from hydroxyl and C1-C6, preferably C1-C4, alkoxy.
R14, R15 and R16 each independently represent a C1-C6 alkyl group, preferably a C1-C4 alkyl group.
Preferred compounds of the invention include:
2-Chloro-5-[2-(2-methoxyethylamino)ethylamino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
[2-[4-Chloro-3-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)carbamoyl-phenylamino]-ethyamino]-acetic acid, hydrochloride,
2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, acetate,
5-[2-(2-Aminoethylamino)ethylamino]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, acetate,
5-[2-(2-Acetylaminoethylamino)ethylamino]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, acetate,
[2-[4-Chloro-3-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)carbamoyl-phenylamino]-ethylamino]-propionic acid,
2-Chloro-5-[2-(2-methylcarbamoylethylamino)ethylamino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, acetate,
2-Chloro-5-[2-(2-dimethylcarbamoylethylamino)ethylamino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, acetate,
2-Chloro-5-[3-(3-hydroxypropylthio)propoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
5-[2-(2-Aminoethylthio)ethoxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[2-(3-hydroxypropylamino)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[3-(3-hydroxypropylsulfonyl)propoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
(xc2x1)-2-Chloro-5-[3-(3-hydroxypropylsulfinyl)propoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylthio)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
(S)-2-Chloro-5-[2-(2-hydroxypropylamino)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
(R)-2-Chloro-5-[2-(2-hydroxypropylamino)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
(S)-2-Chloro-5-[2-(2-hydroxy-1-methylethylamino)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
(R)-2-Chloro-5-[2-(2-hydroxy-1-methylethylamino)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
(xc2x1)-2-Chloro-5-[2-(3-hydroxypropylsulfinyl)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
(xc2x1)-5-[2-(2-Aminoethylsulfinyl)ethoxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
5-[2-(2-Aminoethylsulfonyl)ethoxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
5-[3-(2-Aminoethylthio)propoxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
(xc2x1)-5-[3-(2-Aminoethylsulfinyl)propoxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
5-[3-(2-Aminoethylsulfonyl)propoxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[[2-[(3-hydroxy-3-methylbutyl)amino]ethyl]amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[[2-[[2-(methylthio)ethyl]amino]ethyl]amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[[2-[[2-(methylsulfinyl)ethyl]amino]ethyl]amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, acetic acid salt,
2-Chloro-5-[2-[(2-hydroxy-2-methylpropyl)amino]ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide, dihydrochloride,
2-Chloro-5-[[2-[[2-(1-methyl-1H-imidazol-5-yl)ethyl]amino]ethyl]amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[[2-[[2-(1-methyl-1H-imidazol-4-yl)ethyl]amino)ethyl]amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, and
2-Chloro-5-[[2-[[3-(1H-imidazol-1-yl)propyl]amino]ethyl]amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:
a) when Y represents an oxygen or sulphur atom or a group NR11, reacting a compound of general formula 
wherein L represents a leaving group (e.g. a halogen atom) and D, E, R1, R2, X and R4 are as defined in formula (I), with a compound of general formula
R20xe2x80x94R5xe2x80x94Zxe2x80x83xe2x80x83(IV)
wherein R20 represents xe2x80x94OH, xe2x80x94SH or xe2x80x94NHR11 and R5, R11 and Z are as defined in formula (I); or
b) when Y represents SO or SO2, reacting a corresponding compound of formula (I) in which Y represents a sulphur atom with a suitable oxidising agent;
and optionally after (a) or (b) converting the compound of formula (I) obtained to a pharmaceutically acceptable salt or solvate thereof.
The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as dichloromethane, tetrahydrofuran, or an alcohol such a ethanol, isopropanol or butanol, at a temperature, e.g. in the range from 0 to 200xc2x0 C., preferably in the range from 0 to 150xc2x0 C. The oxidising agent used in (b) above may, for example, be 3-chloroperoxybenzoic acid or potassium peroxymonosulphate, commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d.
Compounds of formula (III) are either known in the art, e.g. from WO 99/29660 and WO 99/29661 or may be prepared easily using known techniques. Compounds of formula (III) wherein X is an oxygen atom can be prepared from the corresponding phenol (WO 99/29660 and WO 99/29661) and a haloalkanol such as 2-chloroethanol, 3-chloropropanol or 4-chlorobutanol in the presence of triphenylphosphine and diethyl azodicarboxylate. Compounds of formula (III) wherein X is an NH group can be prepared from the corresponding aniline (WO 99/29660 and WO 99/29661) and a haloalkanal such as chloroacetaldehyde, 4-chlorobutanal, 5-chloropentanal or an appropriately protected hydroxyalkanal such as 3-tert-butyldimethylsilyloxypropanal in the presence of a reducing agent such as sodium triacetoxyborohydride. In the latter case, removal of the protecting group and activation, for example by conversion into the mesylate group affords compounds of formula (III). Compounds of formula (III) wherein X is a sulfur atom can be prepared from the corresponding thiophenol in the presence of a dihaloalkane such as 1-bromo-2-chloroethane, 1-bromo-3-chloropropane or 1-bromo-4-chlorobutane in the presence of a base such as cesium carbonate.
Compounds of formula (IV) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl, carboxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve at a certain stage the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the present invention are advantageous in that they possess pharmacological activity and have utility as modulators of P2X7 receptor activity. They are therefore indicated as pharmaceuticals for use in the treatment or prevention of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, hyperresponsiveness of the airway, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, glomerulonephritis, irritable bowel disease, Crohn""s disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, neurodegenerative disease, Alzheimer""s disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke, peripheral vascular disease and varicose veins.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, iritable bowel disease, atherosclerosis, psoriasis, pulmonary disease, e.g. COPD or bronchitis, or diseases of the central nervous system, e.g. Alzheimer""s disease or stroke) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disease or condition indicated. For effecting immunosuppression, the daily dosage of the compound of formula (I) will typically be in the range from 0.001 mg/kg to 30 mg/kg.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99%w (percent by weight), more preferably from 0.10 to 70%w, of active ingredient, and, from 1 to 99.95%w, more preferably from 30 to 99.90%w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
The present invention will now be further explained by reference to the following illustrative examples.